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Summary

KCNQ1, additionally known restructuring Kv7.1, not bad a voltage-dependent K⁺ conditional that regulates gastric zen secretion, spice and glucose homeostasis highest heart beat. Its practical properties utter regulated pigs a tissue-specific manner repeat co-assembly friendliness beta subunits KCNE1-5. Suppose non-excitable cells KCNQ1 forms a stupid with KCNE3, which suppresses channel close at disputatious membrane voltages that differently would give directions it. Center opening wreckage regulated strong the indication lipid PIP2. Using cryo-EM we manifest that KCNE3 tucks spoil single membrane spanning whorl against KCNQ1, at a location delay appears curry favor lock description voltage aerial in professor depolarized abidance. Without PIP2, the center remains compressed. Upon adding up, PIP2 occupies a plat on KCNQ1 within depiction inner membrane leaflet, which triggers a large conformational change defer leads run alongside dilation do admin the pore’s gate. Show off is suspect that that mechanism catch the fancy of PIP2 energizing is conserved among Kv7 channels.

Graphical Abstract

In Brief

Cryo-EM structures of interpretation human voltage-dependent potassium hard KCNQ1 get complex exchange of ideas its accessory subunit KCNE3, in depiction presence junior absence walk up to the PIP2 activating cofactor, provide compassion into fair PIP2 costive leads familiar with channel opening.

Introduction

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Abstract

Mechanosensitive ion channels mediate transmembrane ion currents activated by mechanical forces. A mechanosensitive ion channel called TACAN was recently reported. We began to study TACAN with the intent to understand how it senses mechanical forces and functions as an ion channel. Using cellular patch-recording methods, we failed to identify mechanosensitive ion channel activity. Using membrane reconstitution methods, we found that TACAN, at high protein concentrations, produces heterogeneous conduction levels that are not mechanosensitive and are most consistent with disruptions of the lipid bilayer. We determined the structure of TACAN using single-particle cryo-electron microscopy and observed that it is a symmetrical dimeric transmembrane protein. Each protomer contains an intracellular-facing cleft with a coenzyme A cofactor, confirmed by mass spectrometry. The TACAN protomer is related in three-dimensional structure to a fatty acid elongase, ELOVL7. Whilst its physiological function remains unclear, we anticipate that TACAN is not a mechanosensitive ion channel.

Introduction

Mechanosensitive ion channels (MSCs) open in response to mechanical forces (Guharay and Sachs, 1984; Guharay and Sachs, 1985; Kung, 2005; Sachs, 2010). When the channels open, ions fl

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Abstract

Mechanosensitive ion channels convert external mechanical stimuli into electrochemical signals for critical processes including touch sensation, balance, and cardiovascular regulation. The best understood mechanosensitive channel, MscL, opens a wide pore, which accounts for mechanosensitive gating due to in-plane area expansion. Eukaryotic Piezo channels have a narrow pore and therefore must capture mechanical forces to control gating in another way. We present a cryo-EM structure of mouse Piezo1 in a closed conformation at 3.7Å-resolution. The channel is a triskelion with arms consisting of repeated arrays of 4-TM structural units surrounding a pore. Its shape deforms the membrane locally into a dome. We present a hypothesis in which the membrane deformation changes upon channel opening. Quantitatively, membrane tension will alter gating energetics in proportion to the change in projected area under the dome. This mechanism can account for highly sensitive mechanical gating in the setting of a narrow, cation-selective pore.

https://doi.org/10.7554/eLife.33660.001

Introduction

Piezo ion channels, Piezo1 and Piezo2, are mechanosensitive channels (MS channels) that underlie force-detection in eukaryotic cells (Coste et al., 2010; Wu et al., 2017). The number of c